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1.  Resilience does matter: evidence from a 10-year cohort record linkage study 
BMJ Open  2014;4(1):e003917.
To examine 10-year mortality and hospital use among individuals categorised as resilient and vulnerable to the impact of chronic pain.
A cohort record linkage study.
Grampian, Scotland.
5858 individuals from the Grampian Pain Cohort, established in 1996, were linked, by probability matching, with national routinely collected datasets.
Main outcome measures
HRs for subsequent 10-year mortality and ORs/incidence rate ratios for subsequent 10-year hospital use, each with adjustment for potential confounding variables.
36.5% of those with high pain intensity reported a low pain-related disability (categorised resilient) and 7.1% of those reporting low pain intensity reported a high pain-related disability (categorised vulnerable). Sex, age, housing, employment and long-term limiting illness were independently associated with being vulnerable or resilient. After adjustment for these variables, individuals in the resilient group were 25% less likely to die within 10 years of the survey compared with non-resilient individuals: HR 0.75, 95% CI 0.62 to 0.91 and vulnerable individuals were 45% more likely to die than non-vulnerable individuals: HR 1.45, 95% CI 1.01 to 2.11. Resilient individuals were less likely to have had an outpatient or day-case visit for anaesthetics: OR 0.46, 95% CI 0.27 to 0.79, but no other clinical specialities. Vulnerable individuals were significantly less likely to have had any outpatient or day-case visit (OR 0.43, 0.25 to 0.75); but more likely to have had a psychiatric visit (OR 1.96, 1.06 to 3.61). No significant differences in likelihood of any inpatient visits were found.
Resilient individuals have a better 10-year survival than non-resilient individuals indicating that resilience is a phenomenon worth researching. Further research is needed to explore who is likely to become resilient, why and how, as well as to tease out the internal and external factors that influence resilience.
PMCID: PMC3902361  PMID: 24430878
2.  Chronic pain and health status: how do those not using healthcare services fare? 
Relatively little is known about the clinical importance of symptoms not presented to healthcare services. Using data from a community survey we examined the health status among those with chronic pain who reported using or not using healthcare services. Individuals with chronic pain who had used healthcare services in the previous year had poorer health than symptomatic responders who had not used services, irrespective of the severity of chronic pain. The findings suggest that there is little point in trying to detect and treat individuals not currently presenting to healthcare services with their pain.
PMCID: PMC1324844  PMID: 15296563
health services; health services research; health status indicators; pain; signs and symptoms
3.  Assessing the external validity of a randomized controlled trial of anthelminthics in mothers and their children in Entebbe, Uganda 
Trials  2014;15(1):310.
The ‘external validity’ of randomized controlled trials is an important measure of quality, but is often not formally assessed. Trials concerning mass drug administration for helminth control are likely to guide public health policy and careful interpretation of their context is needed. We aimed to determine how representative participants in one such trial were of their community. We explore implications for trial interpretation and resulting public health recommendations.
The trial assessed was the Entebbe Mother and Baby Study (EMaBS), a trial of anthelminthic treatment during pregnancy and early childhood. In a novel approach for assessing external validity, we conducted a two-stage cluster sample community survey within the trial catchment area and compared characteristics of potentially-eligible community children with characteristics of children participating in the trial.
A total of 173 children aged three to five-years-old were surveyed from 480 households. Of children surveyed, we estimated that mothers of 60% would have been eligible for recruitment, and of these, 31% had actually been enrolled. Children surveyed were compared to 199 trial children in the same age group reviewed at annual trial visits during the same time period. There were significant differences in ethnicity between the trial participants and the community children, and in socioeconomic status, with those in the trial having, on average, more educated parents and higher maternal employment. Trial children were less likely to have barefoot exposure and more likely to use insecticide-treated bed nets. There were no significant differences in numbers of reported illness events over the last year.
The trial had not enrolled all eligible participants, and those enrolled were of higher socioeconomic status, and had lower risk of exposure to the parasitic infections targeted by the trial interventions. It is possible the trial may have underestimated the absolute effects of anthelminthic treatment during pregnancy and early childhood, although the fact that there were no differences in reported incidence of common infectious diseases (one of the primary outcomes of EMaBS) between the two groups provides reassurance. Concurrent community surveys may be an effective way to test the external validity of trials.
EMaBS Trial registration
ISRCTN32849447, registered 22 July 2005
PMCID: PMC4138365  PMID: 25100338
Helminths; Anthelminthics; External validity; Generalizability; Cluster sample community survey; Uganda
4.  A Description of Congenital Anomalies Among Infants in Entebbe, Uganda 
BACKGROUND: Data on congenital anomalies from developing countries of the sub-Saharan region are scarce. However, it is important to have comprehensive and reliable data on the description and prevalence of congenital anomalies to allow surveillance and the implementation of appropriate public health strategies for prevention and management. In this study, we describe the profile of congenital anomalies seen in a birth cohort in Entebbe, Uganda. METHODS: Congenital anomalies were defined as any structural defect present at birth. Pregnant women were recruited to the cohort between 2003 and 2005. Defects present at birth were recorded by the midwife at delivery and by physicians at the routine six-week postnatal visit and at illness-related visits until 1 year of life. The anomalies were classified by organ system according to the 10th version of the World Health Organization International Classification of Diseases (ICD-10). RESULTS: There were 180 infants with a congenital anomaly among 2365 births. The most commonly affected systems were the musculoskeletal (42.7 per 1000 births) and skin (16.1 per 1000 births). The prevalence of major anomalies was 20.3 per 1000 births; 1.7 per 1000 births for cardiac anomalies and 1.3 per 1000 births for neural system anomalies. Forty (22%) of the congenital anomalies were identified at birth, 131 (73%) at the 6-week postnatal visit, and nine (5%) at illness-related visits. CONCLUSION: Congenital anomalies are common in developing countries. Establishment of comprehensive databases for surveillance would be helpful for surveillance of effects of new exposures, for prevention, management, and health care planning. Birth Defects Research (Part A) 2011. © 2011 Wiley-Liss, Inc.
PMCID: PMC3272344  PMID: 21770020
congenital anomalies; infants; epidemiology; Uganda; Africa
5.  Radiographic characterization of the hands in Ritscher-Schinzel/3-C syndrome 
SpringerPlus  2013;2:594.
Ritscher-Schinzel Syndrome (RSS) is a clinically variable, autosomal recessive disorder, involving cardiac, cerebellar and craniofacial abnormalities. Numerous reports describe hand changes in RSS patients; however, a detailed characterization of the hands has not previously been performed.
The purpose of this study was to identify whether specific radiographic hand changes were characteristic of RSS and could serve as a diagnostic tool.
Materials and methods
We performed a detailed radiographic hand characterization of 8 RSS patients. The patient population consisted of 5 males and 3 females from ages one month to 26 years, 7 months. The hands were characterized using metacarpophalangeal pattern (MCPP) profiles, carpal height and bone age analyses and assessment of bone morphology.
There was generalized brachydactyly with the second ray being the most severely affected. There was significant shortening of the first metacarpal and the fifth distal phalanx. The MCPP profile generated showed a consistent wavy pattern with average Z-scores ranging from -0.15 (4th proximal phalanx) to -2.13 (1st metacarpal) and 0.53 (4th middle phalanx) to -1.73 (2nd proximal phalanx) for the left and right hands, respectively. Six of eight patients showed a decreased carpal height. Bone age was within normal limits for all patients. Our study population showed consistent radiographic changes including: overtubulation of the bones (especially metacarpals 2-4), prominent tufts of the distal phalanges and a hypoplastic fifth distal phalanx.
The hand findings identified in this study can provide helpful diagnostic tools to clinicians when the diagnosis of RSS is being considered.
PMCID: PMC3830001  PMID: 24255872
Ritscher-Schinzel syndrome; 3-C syndrome; Metacarpophalangeal pattern (MCPP); Profile; Carpal height; Phenotype
6.  Factors affecting the infant antibody response to measles immunisation in Entebbe-Uganda 
BMC Public Health  2013;13:619.
Vaccine failure is an important concern in the tropics with many contributing elements. Among them, it has been suggested that exposure to natural infections might contribute to vaccine failure and recurrent disease outbreaks. We tested this hypothesis by examining the influence of co-infections on maternal and infant measles-specific IgG levels.
We conducted an observational analysis using samples and data that had been collected during a larger randomised controlled trial, the Entebbe Mother and Baby Study (ISRCTN32849447). For the present study, 711 pregnant women and their offspring were considered. Helminth infections including hookworm, Schistosoma mansoni and Mansonella perstans, along with HIV, malaria, and other potential confounding factors were determined in mothers during pregnancy and in their infants at age one year. Infants received their measles immunisation at age nine months. Levels of total IgG against measles were measured in mothers during pregnancy and at delivery, as well as in cord blood and from infants at age one year.
Among the 711 pregnant women studied, 66% had at least one helminth infection at enrolment, 41% had hookworm, 20% M. perstans and 19% S. mansoni. Asymptomatic malaria and HIV prevalence was 8% and 10% respectively. At enrolment, 96% of the women had measles-specific IgG levels considered protective (median 4274 mIU/ml (IQR 1784, 7767)). IgG levels in cord blood were positively correlated to maternal measles-specific IgG levels at delivery (r = 0.81, p < 0.0001). Among the infants at one year of age, median measles-specific IgG levels were markedly lower than in maternal and cord blood (median 370 mIU/ml (IQR 198, 656) p < 0.0001). In addition, only 75% of the infants had measles-specific IgG levels considered to be protective. In a multivariate regression analysis, factors associated with reduced measles-specific antibody levels in infancy were maternal malaria infection, infant malaria parasitaemia, infant HIV and infant wasting. There was no association with maternal helminth infection.
Malaria and HIV infection in mothers during pregnancy, and in their infants, along with infant malnutrition, may result in reduction of the antibody response to measles immunisation in infancy. This re-emphasises the importance of malaria and HIV control, and support for infant nutrition, as these interventions may have benefits for vaccine efficacy in tropical settings.
PMCID: PMC3733798  PMID: 23816281
Infections; Co-infections; Measles; Helminth; Malaria; HIV; Maternal; Infants; Pregnancy; Immunisation
7.  Incongruous consultation behaviour: results from a UK-wide population survey 
BMC Family Practice  2012;13:21.
Symptom characteristics are strong drivers of care seeking. Despite this, incongruous consultation behaviour occurs and has implications for both individuals and health-care services. The aim of this study was to determine how frequently incongruous consultation behaviour occurs, to examine whether it is more common for certain types of symptoms and to identify the factors associated with being an incongruous consulter.
An age and sex stratified random sample of 8,000 adults was drawn from twenty UK general practices. A postal questionnaire was used to collect detailed information on the presence and characteristics of 25 physical and psychological symptoms, actions taken to manage the symptoms, general health, attitudes to symptom management and demographic/socio-economic details. Two types of incongruous consultation behaviour were examined: i) consultation with a GP for symptoms self-rated as low impact and ii) no consultation with a GP for symptoms self-rated as high impact.
A fifth of all symptoms experienced resulted in consultation behaviour which was incongruous based on respondents' own rating of the symptoms' impact. Low impact consultations were not common, although symptoms indicative of a potentially serious condition resulted in a higher proportion of low impact consultations. High impact non-consultations were more common, although there was no clear pattern in the type of associated symptoms. Just under half of those experiencing symptoms in the previous two weeks were categorised as an incongruous consulter (low impact consulter: 8.3%, high impact non-consulter: 37.1%). Employment status, having a chronic condition, poor health, and feeling that reassurance or advice from a health professional is important were associated with being a low impact consulter. Younger age, employment status, being an ex-smoker, poor health and feeling that not wasting the GPs time is important were associated with being a high impact non-consulter.
This is one of the first studies to examine incongruous consultation behaviour for a range of symptoms. High impact non-consultations were common and may have important health implications, particularly for symptoms indicative of serious disease. More research is now needed to examine incongruous consultation behaviour and its impact on both the public's health and health service use.
PMCID: PMC3338366  PMID: 22433072
Signs & symptoms; Community-based; Health care services; Primary care
8.  Ascertaining the size of the symptom iceberg in a UK-wide community-based survey 
The symptom iceberg describes the phenomenon that most symptoms are managed in the community without people seeking professional health care. The size of the iceberg for many symptoms is unknown, as is their association with personal characteristics, including history of a chronic disease.
To ascertain the size of the symptom iceberg in the UK.
Design of study
A UK-wide community-based postal survey.
Urban and rural communities across the UK.
A postal survey was sent to an age- and sex-stratified random sample of 2474 adults, aged 18–60 years, drawn from 20 practices around the UK. Questions were aimed at investigating adults' experiences of 25 different symptoms in the previous 2 weeks.
The number of symptoms experienced by one individual in the previous 2 weeks ranged from 0 to 22 (mean 3.66). Of the symptoms examined, the three most common were: feeling tired/run down; headaches; and joint pain. Univariate analysis found symptom prevalence to be significantly associated with a wide range of participant characteristics. However, after adjustment, many of these associations no longer remained significant for a number of the symptoms. Presence of a chronic condition, age, and employment status were the three factors most commonly associated with the 2-week prevalence of symptoms. Reported symptom characteristics (severity, duration, interference, and time off work) varied little by sex or age.
Symptoms in the UK community are common. Symptom prevalence was associated with a number of participant characteristics, although the extent of this association was less than has been reported in previous research. This study provides an important current baseline prevalence of 25 symptoms in the community for those who do, and do not, have a chronic condition.
PMCID: PMC3020067  PMID: 21401979
community-based; epidemiology; prevalence; signs and symptoms; symptom iceberg
9.  Parasite infection is associated with Kaposi's sarcoma associated herpesvirus (KSHV) in Ugandan women 
Immune modulation by parasites may influence susceptibility to bacteria and viruses. We examined the association between current parasite infections, HIV and syphilis (measured in blood or stool samples using standard methods) and antibodies against Kaposi's sarcoma herpesvirus (KSHV), measured by ELISA, in 1915 stored plasma samples from pregnant women in Entebbe, Uganda.
Seroprevalence of KSHV was higher in women with malaria parasitaemia (73% vs 60% p = 0.01), hookworm (67% vs 56% p = 0.001) and Mansonella perstans (69% vs 59% p = 0.05); seroprevalence increased with increasing intensity of hookworm infection (p < 0.001[trend]). No associations were found for HIV, five other parasites or active syphilis. These effects were not explained by socioeconomic status or education.
Specific parasite infections are associated with presence of antibodies against KSHV, perhaps mediated via their effect on immune function.
PMCID: PMC3197512  PMID: 21962023
10.  Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on immune responses to schistosome antigens among the offspring: results of a randomised, placebo-controlled trial 
BMC Infectious Diseases  2011;11:234.
Offspring of women with schistosomiasis may exhibit immune responsiveness to schistosomes due to in utero sensitisation or trans-placental transfer of antibodies. Praziquantel treatment during pregnancy boosts maternal immune responses to schistosome antigens and reduces worm burden. Effects of praziquantel treatment during pregnancy on responses among offspring are unknown.
In a trial of anthelminthic treatment during pregnancy in Uganda (ISRCTN32849447;, offspring of women with Schistosoma mansoni were examined for cytokine and antibody responses to schistosome worm (SWA) and egg (SEA) antigen, in cord blood and at age one year. Relationships to maternal responses and pre-treatment infection intensities were examined, and responses were compared between the offspring of women who did, or did not receive praziquantel treatment during pregnancy.
Of 388 S. mansoni-infected women studied, samples were obtained at age one year from 215 of their infants. Stool examination for S. mansoni eggs was negative for all infants. Cord and infant samples were characterised by very low cytokine production in response to schistosome antigens with the exception of cord IL-10 responses, which were substantial. Cord and infant cytokine responses showed no association with maternal responses. As expected, cord blood levels of immunoglobulin (Ig) G to SWA and SEA were high and correlated with maternal antibodies. However, by age one year IgG levels had waned and were hardly detectable. Praziquantel treatment during pregnancy showed no effect on cytokine responses or antibodies levels to SWA or SEA either in cord blood or at age one year, except for IgG1 to SWA, which was elevated in infants of treated mothers, reflecting maternal levels. There was some evidence that maternal infection intensity was positively associated with cord blood IL-5 and IL-13 responses to SWA, and IL-5 responses to SEA, and that this association was modified by treatment with praziquantel.
Despite strong effects on maternal infection intensity and maternal immune responses, praziquantel treatment of infected women during pregnancy had no effect on anti-schistosome immune responses among offspring by age one year. Whether the treatment will impact upon the offspring's responses on exposure to primary schistosome infection remains to be elucidated.
Trial registration
PMCID: PMC3176493  PMID: 21888656
11.  Impact of lifestyle in middle-aged women on mortality: evidence from the Royal College of General Practitioners' Oral Contraception Study 
Although many individuals have multiple lifestyle risk factors, few studies have investigated the impact of lifestyle risk factor combinations among women.
To investigate the relationship between individual and combinations of lifestyle risk factors in middle-aged women with subsequent mortality, and to estimate the associated population attributable risks.
Design of study
Prospective cohort study.
Royal College of General Practitioners' (RCGP) Oral Contraception Study, UK.
In 1994–1995, women remaining under follow-up in the RCGP Oral Contraception Study were sent a lifestyle survey, from which modifiable risk factors were identified: pack-years smoked, physical inactivity, never drinking versus consuming at least 7 units of alcohol weekly, and being underweight, overweight, or obese. The cohort was followed to December 2006 or death. Population attributable risks were calculated.
Of 10 059 women studied, 896 died. Pack-years smoked (11–20 years: adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.46 to 2.27; >20 years: adjusted HR = 2.34, 95% CI = 2.00 to 2.74); never drinking alcohol (adjusted HR = 1.66, 95% CI = 1.34 to 2.05); being underweight (adjusted = HR 1.66, 95% CI = 1.03 to 2.68); and physical inactivity (<15 hours/week: adjusted HR = 1.73, 95% CI = 1.46 to 2.04) were significantly associated with mortality compared with their respective reference group. Women with multiple lifestyle risk factors had higher mortality risks than those reporting one factor. The population attributable risk of the combination of smoking, physical inactivity, body mass index outside normal range, and alcohol (never drinking or excess intake) was 59% (95% CI = 31% to 78%).
Assuming a causal relationship between lifestyle and mortality, avoidance of four lifestyle risk factors would have prevented 60% of the deaths. The importance of avoiding smoking and undertaking physical inactivity during midlife should continue to be emphasised.
PMCID: PMC2913736  PMID: 20822689
epidemiology; follow-up studies; lifestyle; mortality; women
12.  Revisiting the symptom iceberg in today's primary care: results from a UK population survey 
BMC Family Practice  2011;12:16.
Recent changes in UK primary care have increased the range of services and healthcare professionals available for advice. Furthermore, the UK government has promoted greater use of both self-care and the wider primary care team for managing symptoms indicative of self-limiting illness. We do not know how the public has been responding to these strategies. The aim of this study was to describe the current use of different management strategies in the UK for a range of symptoms and identify the demographic, socio-economic and symptom characteristics associated with these different approaches.
An age and sex stratified random sample of 8,000 adults (aged 18-60), drawn from twenty general practices across the UK, were sent a postal questionnaire. The questionnaire collected detailed information on 25 physical and psychological symptoms ranging from those usually indicative of minor illness to those which could be indicative of serious conditions. Information on symptom characteristics, actions taken to manage the symptoms and demographic/socio-economic details were also collected.
Just under half of all symptoms reported resulted in respondents doing nothing at all. Lay-care was used for 35% of symptoms and primary care health professionals were consulted for 12% of symptoms. OTC medicine use was the most common lay-care strategy (used for 25% of all symptom episodes). The GP was the most common health professional consulted (consulted for 8% of all symptom episodes) while use of other primary care health professionals was very small (each consulted for less than 2% of symptom episodes). The actions taken for individual symptoms varied substantially although some broad patterns emerged. Symptom characteristics (in particular severity, duration and interference with daily life) were more commonly associated with actions taken than demographic or socio-economic characteristics.
While the use of lay-care was widespread, use of the primary care team other than the GP was low. Further research is needed to examine the public's knowledge and opinions of different primary care services to investigate why certain services are not being used to inform the future development of primary care services in the UK.
PMCID: PMC3083353  PMID: 21473756
Signs and symptoms; Symptom iceberg; Community-based; Health care services; Primary care
13.  Authors’ reply 
BMJ : British Medical Journal  2008;336(7635):60.
PMCID: PMC2190231
14.  Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial 
Lancet  2011;377(9759):52-62.
Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections.
In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447.
Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment.
These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed.
Wellcome Trust.
PMCID: PMC3018567  PMID: 21176950
15.  Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study 
Objective To see if the mortality risk among women who have used oral contraceptives differs from that of never users.
Design Prospective cohort study started in 1968 with mortality data supplied by participating general practitioners, National Health Service central registries, or both.
Setting 1400 general practices throughout the United Kingdom.
Participants 46 112 women observed for up to 39 years, resulting in 378 006 woman years of observation among never users of oral contraception and 819 175 among ever users.
Main outcome measures Directly standardised adjusted relative risks between never and ever users for all cause and cause specific mortality.
Results 1747 deaths occurred in never users of oral contraception and 2864 in ever users. Compared with never users, ever users of oral contraception had a significantly lower rate of death from any cause (adjusted relative risk 0.88, 95% confidence interval 0.82 to 0.93). They also had significantly lower rates of death from all cancers; large bowel/rectum, uterine body, and ovarian cancer; main gynaecological cancers combined; all circulatory disease; ischaemic heart disease; and all other diseases. They had higher rates of violent deaths. No association between overall mortality and duration of oral contraceptive use was observed, although some disease specific relations were apparent. An increased relative risk of death from any cause between ever users and never users was observed in women aged under 45 years who had stopped using oral contraceptives 5-9 years previously but not in those with more distant use. The estimated absolute reduction in all cause mortality among ever users of oral contraception was 52 per 100 000 woman years.
Conclusion Oral contraception was not associated with an increased long term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral contraception usage and background risk of disease.
PMCID: PMC2837145  PMID: 20223876
16.  Effect of praziquantel treatment of Schistosoma mansoni during pregnancy on intensity of infection and antibody responses to schistosome antigens: results of a randomised, placebo-controlled trial 
Praziquantel treatment of schistosomiasis during pregnancy was only recommended in 2002; hence the effects of treatment during pregnancy are not fully known. We have therefore evaluated the effects on infection intensity and the immunological effects of praziquantel treatment against Schistosoma mansoni during pregnancy, compared with treatment after delivery.
A nested cohort of 387 Schistosoma mansoni infected women was recruited within a larger trial of de-worming during pregnancy. Women were randomised to receive praziquantel or placebo during pregnancy. All women were treated after delivery. Infection intensity after treatment was assessed by a single Kato-Katz examination of stool samples with duplicate slides and categorised as undetected, light (1–99 eggs per gram (epg)), moderate (100–399 epg) or heavy (≥400 epg). Antibodies against S. mansoni worm and egg antigens were measured by ELISA. Results were compared between women first treated during pregnancy and women first treated after delivery.
At enrolment, 252 (65.1%) of the women had light infection (median (IQR) epg: 35 (11, 59)), 75 (19.3%) moderate (median (IQR) epg: 179(131, 227)) and 60 (15.5%) had heavy infection (median (IQR) epg: 749 (521, 1169)) with S. mansoni. At six weeks after praziquantel treatment during pregnancy S. mansoni infection was not detectable in 81.9% of the women and prevalence and intensity had decreased to 11.8% light, 4.7% moderate and 1.6% heavy a similar reduction when compared with those first treated after delivery (undetected (88.5%), light (10.6%), moderate (0.9%) and heavy (0%), p = 0.16). Parasite specific antibody levels were lower during pregnancy than after delivery. Praziquantel treatment during pregnancy boosted anti-worm IgG isotypes and to a lesser extent IgE, but these boosts were less pronounced than in women whose treatment was delayed until after delivery. Praziquantel had limited effects on antibodies against egg antigens.
S mansoni antigen-specific antibody levels and praziquantel-induced boosts in antibody levels were broadly suppressed during pregnancy, but this was not associated with major reduction in the efficacy of praziquantel. Long-term implications of these findings in relation to resistance to re-infection remain to be explored.
Trial registration
International Standard Randomised Controlled Trial Number for the current study: ISRCTN32849447
PMCID: PMC2666740  PMID: 19296834
17.  The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447] 
Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects "spill-over", altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life.
To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood.
The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 X 2(x2) factorial design.
Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed.
This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy. Clinical Trials 2007; 4: 42–57.
PMCID: PMC2643383  PMID: 17327245
18.  Uptake of HIV and syphilis testing of pregnant women and their male partners in a programme for prevention of mother-to-child HIV transmission in Uganda 
To describe uptake of HIV and syphilis testing in a prevention of mother-to-child HIV transmission programme in Uganda.
Analysis of data from routine HIV and syphilis testing at Entebbe Hospital antenatal services.
A total of 20 738 women attended antenatal services. Exactly 62.8% of women, but only 1.8% of their male partners, accepted testing for HIV; 82.2% of women, but only 1.1% of their male partners accepted syphilis testing. Partners of women with positive HIV results were more likely to come for subsequent testing. Of 200 couples whose partners accepted HIV-testing within 30 days of one another, 19 (9.5%) were HIV-discordant, representing 65.5% of couples with at least one partner HIV-positive. HIV prevalence was 12.6% for women and 10.8% for men; syphilis prevalence was 4.0% for women and 6.2% for men.
Uptake of HIV and syphilis testing was fairly good among pregnant women attending antenatal clinics at Entebbe Hospital, but very low among their male partners. The level of HIV-discordant couples was high. These clinics should be made more couples-friendly to identify both HIV-positive men for treatment and discordant couples for HIV prevention.
PMCID: PMC2592475  PMID: 18331533
HIV; PMTCT; Uganda; pregnant; couple; syphilis
19.  Use of antenatal services and delivery care in Entebbe, Uganda: a community survey 
Disparities in perinatal health care occur worldwide. If the UN Millennium Development Goals in maternal and child health are to be met, this needs to be addressed. This study was conducted to facilitate our understanding of the changing use of maternity care services in a semi-urban community in Entebbe Uganda and to examine the range of antenatal and delivery services received in health care facilities and at home.
We conducted a retrospective community survey among women using structured questionnaires to describe the use of antenatal services and delivery care.
In total 413 women reported on their most recent pregnancy. Antenatal care attendance was high with 96% attending once, and 69% the recommended four times. Blood pressure monitoring (95%) and tetanus vaccination (91%) were the services most frequently reported and HIV testing (47%), haematinics (58%) and presumptive treatment for malaria (66%) least frequently. Hospital clinics significantly outperformed public clinics in the quality of antenatal service. A significant improvement in the reported quality of antenatal services received was observed by year (p < 0.001). Improvement in the range and consistency of services at Entebbe Hospital over time was associated with an increase in the numbers who sought care there (p = 0.038). Although 63% delivered their newborn at a local hospital, 11% still delivered at home with no skilled assistance and just under half of these women reported financial/transportation difficulties as the primary reason. Less educated, poorer mothers were more likely to have unskilled/no assistance. Simple newborn care practices were commonly neglected. Only 35% of newborns were breastfed within the first hour and delayed wrapping of newborn infants occurred after 27% of deliveries.
Although antenatal services were well utilised, the quality of services varied. Women were able and willing to travel to a facility providing a good service. Access to essential skilled birth attendants remains difficult especially for less educated, poorer women, commonly mediated by financial and transport difficulties and several simple post delivery practices were commonly neglected. These factors need to be addressed to ensure that high quality care reaches the most vulnerable women and infants.
PMCID: PMC2098779  PMID: 17931422
20.  Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study 
BMJ : British Medical Journal  2007;335(7621):651.
Objective To examine the absolute risks or benefits on cancer associated with oral contraception, using incident data.
Design Inception cohort study.
Setting Royal College of General Practitioners' oral contraception study.
Participants Directly standardised data from the Royal College of General Practitioners' oral contraception study.
Main outcome measures Adjusted relative risks between never and ever users of oral contraceptives for different types of cancer, main gynaecological cancers combined, and any cancer. Standardisation variables were age, smoking, parity, social class, and (for the general practitioner observation dataset) hormone replacement therapy. Subgroup analyses examined whether the relative risks changed with user characteristics, duration of oral contraception usage, and time since last use of oral contraception.
Results The main dataset contained about 339 000 woman years of observation for never users and 744 000 woman years for ever users. Compared with never users ever users had statistically significant lower rates of cancers of the large bowel or rectum, uterine body, and ovaries, tumours of unknown site, and other malignancies; main gynaecological cancers combined; and any cancer. The relative risk for any cancer in the smaller general practitioner observation dataset was not significantly reduced. Statistically significant trends of increasing risk of cervical and central nervous system or pituitary cancer, and decreasing risk of uterine body and ovarian malignancies, were seen with increasing duration of oral contraceptive use. Reduced relative risk estimates were observed for ovarian and uterine body cancer many years after stopping oral contraception, although some were not statistically significant. The estimated absolute rate reduction of any cancer among ever users was 45 or 10 per 100 000 woman years, depending on whether the main or general practitioner observation dataset was used.
Conclusion In this UK cohort, oral contraception was not associated with an overall increased risk of cancer; indeed it may even produce a net public health gain. The balance of cancer risks and benefits, however, may vary internationally, depending on patterns of oral contraception usage and the incidence of different cancers.
PMCID: PMC1995533  PMID: 17855280
21.  Symptom experience and subsequent mortality: results from the West of Scotland Twenty-07 study 
Associations between symptom experience and mortality have rarely been investigated. One study has suggested that the number of symptoms people experience may be an important predictor of mortality. This novel and potentially important finding may have important implications but needs to be tested in other cohorts.
858 people aged around 58 years were interviewed by nurses in 1990/1 as part of the West of Scotland Twenty-07 Study. They were asked about the presence of symptoms in the last month from a checklist of 33 symptoms. Measures of morbidity included symptom type (respiratory, musculoskeletal, gastrointestinal, mental health, neurological, systemic) and symptom summary measures looking at the number and impact of symptoms (total number; number participants tended to have; number participants did not tend to have; number which restricted usual activities; number which led to GP consultation). Hazard ratios for thirteen-year all-cause mortality were calculated for symptom types, symptom summary measures, and self-assessed health with and without adjustment.
On unadjusted analysis, and after adjusting for gender, socio-economic status and smoking, mortality was elevated in individuals reporting respiratory, systemic and mental health symptoms. After additional adjustment for chronic conditions and self-assessed health, only the association between mental health symptoms and mortality remained significant. On unadjusted analysis, and after adjusting for gender, socio-economic status and smoking, mortality was elevated in individuals with many (≥ 6) symptoms in four of the symptom summary measures examined. These relationships were no longer significant after additional adjustment for chronic conditions and self-assessed health. A clear trend of increasing mortality as self-assessed health became poorer was observed. This pattern remained statistically significant after adjustment for gender, socio-economic status, smoking, chronic conditions and the total number of symptoms experienced.
Symptoms often thought of as minor may have important consequences later in life especially for those reporting mental health-related symptoms or those experiencing many symptoms. In this study however, self-assessed health appeared to be a better predictor of mortality than the type or number of symptoms experienced, even when the tendency to have and impact of the symptoms were taken into account.
PMCID: PMC1702541  PMID: 17156478
22.  Experiences and perceptions of people with headache: a qualitative study 
BMC Family Practice  2006;7:27.
Few qualitative studies of headache have been conducted and as a result we have little in-depth understanding of the experiences and perceptions of people with headache. The aim of this paper was to explore the perceptions and experiences of individuals with headache and their experiences of associated healthcare and treatment.
A qualitative study of individuals with headache, sampled from a population-based study of chronic pain was conducted in the North-East of Scotland, UK. Seventeen semi-structured interviews were conducted with adults aged 65 or less. Interviews were analysed using the Framework approach utilising thematic analysis.
Almost every participant reported that they were unable to function fully as a result of the nature and unpredictability of their headaches and this had caused disruption to their work, family life and social activities. Many also reported a negative impact on mood including feeling depressed, aggressive or embarrassed. Most participants had formed their own ideas about different aspects of their headache and several had searched for, or were seeking, increased understanding of their headache from a variety of sources. Many participants reported that their headaches caused them constant worry and anguish, and they were concerned that there was a serious underlying cause. A variety of methods were being used to manage headaches including conventional medication, complementary therapies and self-developed management techniques. Problems associated with all of these management strategies emerged.
Headache has wide-ranging adverse effects on individuals and is often accompanied by considerable worry. The development of new interventions or educational strategies aimed at reducing the burden of the disorder and associated anxiety are needed.
PMCID: PMC1523257  PMID: 16670013
23.  A randomised controlled trial of the effects of albendazole in pregnancy on maternal responses to mycobacterial antigens and infant responses to bacille Calmette-Guérin (BCG) immunisation [ISRCTN32849447] 
Maternal schistosomiasis and filariasis have been shown to influence infant responses to neonatal bacille Calmette-Guérin (BCG) immunisation but the effects of maternal hookworm, and of de-worming in pregnancy, are unknown.
In Entebbe, Uganda, we conducted a randomised, double-blind, placebo-controlled trial of a single dose of 400 mg of albendazole in the second trimester of pregnancy. Neonates received BCG. Interferon-gamma (IFN-γ) and interleukin (IL)-5 responses to a mycobacterial antigen (crude culture filtrate proteins (CFP) of Mycobacterium tuberculosis) were measured in a whole blood assay. We analysed results for binary variables using χ2 tests and logistic regression. We analysed continuous variables using Wilcoxon's tests.
Maternal hookworm was associated with reduced maternal IFN-γ responses to CFP (adjusted odds ratio for IFN-γ > median response: 0.14 (95% confidence interval 0.02–0.83, p = 0.021). Conversely, maternal hookworm was associated with subsequent increased IFN-γ responses in their one-year-old infants (adjusted OR 17.65 (1.20–258.66; p = 0.013)). Maternal albendazole tended to reduce these effects.
Untreated hookworm infection in pregnancy was associated with reduced maternal IFN-γ responses to mycobacterial antigens, but increased responses in their infants one year after BCG immunisation. The mechanisms of these effects, and their implications for protective immunity remain, to be determined.
PMCID: PMC1352364  PMID: 16371154
24.  Long term effects of hysterectomy on mortality: nested cohort study 
BMJ : British Medical Journal  2005;330(7506):1482.
Objectives To investigate the long term risk (mean > 20 years) of death from all causes, cardiovascular disease, and cancer in women who had or had not had a hysterectomy.
Design Nested cohort study.
Setting Royal College of General Practitioners' oral contraception study.
Participants 7410 women (3705 flagged at the NHS central registries for cancer and death who had a hysterectomy during the oral contraception study and 3705 who were flagged but did not have the operation).
Main outcome measures Mortality from all causes, cardiovascular disease, and cancer.
Results 623 (8.4%) women had died by the end of follow-up (308 in the hysterectomy group and 315 in the non-hysterectomy group). Older women who had had a hysterectomy had a 6% reduced risk of death compared with women of a similar age who did not have the operation (adjusted hazard ratio 0.94, 95% confidence interval 0.75 to 1.18). Compared with young women who did not have a hysterectomy those who were younger at hysterectomy had an adjusted hazard ratio for all cause mortality of 0.82 (0.65 to 1.03). Hysterectomy was not associated with a significantly altered risk of mortality from cardiovascular disease or cancer regardless of age.
Conclusion Hysterectomy did not increase the risk of death in the medium to long term.
PMCID: PMC558457  PMID: 15930026
25.  Increased mortality among women with Rose angina who have not presented with ischaemic heart disease. 
BACKGROUND: Little is known about the clinical importance of disease that is not presented to healthcare services. AIM: To determine the 5-year mortality among those with angina symptoms, known or not known by their general practitioner (GP) to have ischaemic heart disease (IHD). DESIGN: A prospective cohort study. SETTING: The study was conducted in the United Kingdom as part of the Royal College of General Practitioners' Oral Contraception Study. METHOD: In 1994-1995 women (n = 11,797) still under GP observation were sent a questionnaire that inquired about their smoking habits, other lifestyle issues, general health, and selected symptoms (including chest pain, assessed using the Rose angina questionnaire). The main outcome measure was the chances (odds) of dying during the next 5 years, among those with and without exertional chest pain, Rose angina or Rose myocardial infarction (MI), stratified by documented history of IHD. RESULTS: Overall, the lifetime prevalence of any exertional chest pain was 10.1% (95% confidence interval [CI] = 9.5 to 10.8); grade I Rose angina was 6.1% (95% CI = 5.6 to 6.6); grade II Rose angina was 1.3% (95% CI = 1.1 to 1.6); and Rose MI was 4.4% (95% CI = 4.0 to 4.9). The prevalence of each condition tended to increase with age, social class, parity, body mass index, and documented history of IHD. The proportion of women documented as having IHD was 23% among those with any exertional chest pain, 21.7% for grade I Rose angina, 37.7% for grade II Rose angina, and 31.4% for Rose MI. Compared to women without Rose angina, significantly higher odds ratios for all-cause mortality were observed among women with grade I Rose angina and no documented history of IHD (adjusted odds ratio [AOR] = 1.71, 95% CI = 1.05 to 2.79); those with grade II Rose angina and documented IHD (AOR = 3.94, 95% CI = 1.58 to 9.83); and women with grade II Rose angina and no documented history of IHD (AOR = 3.35, 95% CI = 1.47 to 7.62). CONCLUSIONS: Women with angina symptoms that have not been documented by their GP appear to have an increased risk of future mortality. Research is needed to determine the best way of identifying and managing these individuals.
PMCID: PMC1314711  PMID: 14601354

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